Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
  • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
  • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
  • A01N37/46—N-acyl derivatives
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
  • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/275—Nitriles; Isonitriles
  • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
  • A61P33/06—Antimalarials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/14—Ectoparasiticides, e.g. scabicides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

• the present invention relates to a composition for exterminating an animal parasite and a method for exterminating an animal parasite.
• conventional parasiticides for administration to an animal to exterminate animal parasites include formulations of imidacloprid, fipronil, etc.
• WO2005/073165 discusses insecticides compounds similar to the compounds of the present invention. WO2005/073165 does not disclose methods of treatment or methods of killing parasites using the compounds similar to the present invention disclosed therein.
• WO 2000/55120 , WO 2000/7980 and US 2002-032238 each describe a compound similar to the compounds of the present invention.
• the compounds in these documents clearly do not fall within the scope of claims of the present invention. Additionally, none of the documents disclose parasiticidal activity of the compound.
• an objective of the invention is to provide a composition that has excellent activity for exterminating animal parasites, and a method for exterminating animal parasites.
• an aromatic carboxamide derivative represented by Formula (1) of the present invention and a composition containing the present aromatic carboxamide derivative as an active ingredient have excellent activity for exterminating animal parasites, thereby completing the present invention.
• the present invention is as follows.
• composition which has excellent activity for exterminating animal parasites for use in a method for exterminating animal parasites is provided.
• a composition for exterminating animal parasites according to the present invention includes at least one amide derivative represented by the following Formula (1).
• Q 1 represents a phenyl group or a phenyl group substituted with a halogen atom.
• X 1 represents a fluorine atom
• X 2 , X 3 , and X 4 each represent a hydrogen atom.
• R 1 represents a hydrogen atom or a C1-C3 alkyl group
• R 2 represents a hydrogen atom.
• Y 1 and Y 5 each independently represent a halogen atom or a C1-C3 haloalkyl group
• Y 2 and Y 4 each represent a hydrogen atom
• Y 3 represents a heptafluoroisopropyl group.
• halogen atom represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
• C1-C3 means the number of carbon atoms of from 1 to 3
• C2-C6 means the number of carbon atoms of from 2 to 6.
• C1-C3 alkyl group in the present invention represents, for example, a linear or branched alkyl group having from 1 to 3 carbon atoms such as methyl, ethyl, n-propyl, or i-propyl.
• C1-C3 haloalkyl group represents, for example, a linear or branched alkyl group having from 1 to 3 carbon atoms, that is substituted with one or more halogen atoms which may be the same as or different from each other, such as trifluoromethyl, pentafluoroethyl, heptafluoro-n-propyl, heptafluoro-i-propyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 1,3-difluoro-2-propyl.
• halogen atoms which may be the same as or different from each other, such as trifluoromethyl, pentafluor
• 1,3-dichloro-2-propyl 1-chloro-3-fluoro-2-propyl, 1,1,1-trifluoro-2-propyl, 3,3,3-trifluoro-n-propyl 1,1,1,3,3,3-hexafluoro-2-propyl, 1,1,1,3,3,3-hexafluoro-2-chloro-2-propyl, 1,1,1,3,3,3-hexafluoro-2-bromo-2-propyl, 1,1,2,3,3,3-hexafluoro-2-chloro-n-propyl, 1,1,2,3,3,3-hexafluoro-2-bromo-n-propyl, 1,1,2,3,3,3-hexafluoro-1-bromo-2-propyl, 2,2,3,3,3-pentafluoro-n-propyl, 3-fluoro-n-propyl, 3-chloro-n-propyl, or 3-bromo-n-propyl.
• C1-C6 alkyl group in the present invention represents, for example, a linear or branched alkyl group having from 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, neopentyl, 4-methyl-2-pentyl, n-hexyl, or 3- methyl-n-pentyl
• C3-C9 cycloalkyl group represents, for example, a cycloalkyl group having from 3 to 9 carbon atoms, that has a cyclic structure, such as cyclopropyl, cyclobutyl, cyclopentyl, 2-methylcyclopentyl, 3-methylcyclopentyl, cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, or 4-methylcyclohexyl.
• C2-C6 alkenyl group represents, for example, an alkenyl group having from 2 to 6 carbon atoms, that has a double bond in the carbon chain, such as vinyl, allyl, 2-butenyl, or 3-butenyl
• C2-C6 alkynyl group represents, for example, an alkynyl group having from 2 to 6 carbon atoms, that has a triple bond in the carbon chain, such as propargyl, 1-butyn-3-yl, or 1-butyn-3-methyl-3-yl
• the amide derivatives represented by Formula (1) according to the present invention may include one or plural chiral carbon atoms or chiral centers in their structural Formulae, and thus two or more optical isomers may exist. However, the present invention includes each of the optical isomers and a mixture thereof at any proportions. Further, the amide derivative represented by Formula (1) according to the present invention may include two or more kinds of geometrical isomers derived from carbon-carbon double bonds in the structural Formulae. The present invention includes each of the geometrical isomers and a mixture thereof at any proportions.
• X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , Q 1 , Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 represent the same definitions as X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , Q 1 , Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 , respectively, in Formula (1).
• LG represents a functional group having a leaving ability, such as a halogen atom, or a hydroxy group
• Hal represents a chlorine atom or a bromine atom
• Xa and Xb represent chlorine atoms, bromine atoms, or iodine atoms.
• R 3 represents a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group.
• a nitro aromatic carboxamide derivative represented by Formula (13) can be prepared by reacting a nitro aromatic carboxylic acid derivative having a leaving group represented by Formula (11) with an aromatic amine derivative represented by Formula (12) in a suitable solvent or without a solvent.
• a suitable base can be used.
• the solvent may be any of those which do not inhibit the present reaction significantly.
• examples thereof may include water and aromatic hydrocarbons such as benzene, toluene, or xylene, halogenated hydrocarbons such as dichloromethane, chloroform, or carbon tetrachloride chained or cyclic ethers such as diethyl ether, dioxane, tetrahydrofuran, or 1,2-dimethoxy ethane esters such as ethyl acetate, or butyl acetate alcohols such as methanol, or ethanol ketones such as acetone, methyl isobutyl ketone, or cyclohexenone amides such as dimethyl formamide, or dimethylacetamide nitriles such as acetonitrile and inert solvents such as 1,3-dimethyl-2-imidazolidinone.
• aromatic hydrocarbons such as benzene, toluene, or xylene
• examples of the base may include organic bases such as triethylamine, tri-n-butyl amine, pyridine, or 4-dimethylamino pyridine, alkali metal hydroxides such as sodium hydroxide, or potassium hydroxide, carbonates such as sodium hydrogen carbonate, or potassium carbonate phosphates such as dipotassium monohydrogen phosphate, or trisodium phosphate alkali metal hydride salts such as sodium hydride alkali metal alkoxides such as sodium methoxide, or sodium ethoxide, and lithium amides such as lithium diisopropyl amide,
• organic bases such as triethylamine, tri-n-butyl amine, pyridine, or 4-dimethylamino pyridine
• alkali metal hydroxides such as sodium hydroxide, or potassium hydroxide
• carbonates such as sodium hydrogen carbonate, or potassium carbonate phosphates such as dipotassium monohydrogen phosphate
• bases may be appropriately used in an amount in the range from 0.01-fold molar equivalent to 5-fold molar equivalents with respect to the compound represented by Formula (11).
• the reaction temperature may be appropriately selected from -20°C to the reflux temperature of the solvent used. Further, the reaction time may be appropriately selected within the range from several minutes to 96 hours.
• the aromatic carbonyl halide derivative can be prepared easily by a general method using a halogenating agent from an aromatic carboxylic acid.
• a halogenating agent examples include thionyl chloride, thionyl bromide, phosphorus oxychloride, oxalyl chloride, or phosphorus trichloride.
• the compound represented by Formula (13) from the nitro aromatic carboxylic acid derivative and the compound represented by Formula (12) without using a halogenating agent.
• the method may include a method described in, for example, Chem. Ber. p. 788 (1970 ), in which a condensing agent such as N,N'-dicyclohexylcarbodiimide is appropriately used, suitably with the use of an additive such as 1-hydroxybenzotriazole.
• Other condensing agents that can be used in this case may include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, or 1,1'-carbonylbis-1H-imidazole,
• examples of other methods for producing the compound represented by Formula (13) may include a mixed acid anhydride method using chloroformic acid esters, and examples thereof include a method described in J. Am. Chem. Soc., p. 5012 (1967 ), whereby the compound represented by Formula (13) can be prepared.
• Examples of the chloroformic acid esters used in this case may include isobutyl chloroformate, or isopropyl chloroformate.
• chloroformic acid esters diethylacetyl chloride, or trimethylacetyl chloride may also be included.
• Both the method using a condensing agent and the mixed acid anhydride method are not limited by the solvent, the reaction temperature, and the reaction time according to the literature above.
• An inert solvent may be used which does not inhibit the progress of the appropriate reaction significantly, and the reaction temperature and the reaction time may also be selected appropriately according to the progress of the reaction.
• An aromatic carboxamide derivative having an amino group represented by Formula (14) can be derived from the aromatic carboxamide derivative having a nitro group represented by Formula (13) by means of a reduction reaction.
• Examples of such reduction include a method using a hydrogenation reaction and a method using a metal compound (for example, stannous chloride (anhydride), iron powder, or zinc powder).
• the reaction of the former method can be carried out in a suitable solvent in the presence of a catalyst at normal pressure or a higher pressure under a hydrogen atmosphere.
• a catalyst may include palladium catalysts such as palladium-carbon and the like, nickel catalysts such as Raney-nickel, cobalt catalysts, ruthenium catalysts, rhodium catalysts, or platinum catalysts and examples of the solvent may include water; alcohols such as methanol, or ethanol; aromatic hydrocarbons such as benzene, or toluene; chained or cyclic ethers such as ether, dioxane, or tetrahydrofuran; and esters such as ethyl acetate.
• the pressure may be appropriately selected within a range of 0.1 MPa to 10 MPa
• the reaction temperature may be appropriately selected within a range of -20°C to the reflux temperature of the solvent used
• the reaction time may be appropriately selected within a range of several minutes to 96 hours, whereby the compound of Formula (14) can be efficiently prepared.
• Examples of the latter method include a method using stannous chloride (anhydride) as a metal compound under the conditions described in "Organic Syntheses" Coll. Vol. III, P. 453.
• a compound represented by Formula (15) can be prepared by reacting the compound represented by Formula (14) with an aldehyde or a ketone in a solvent, and reacting them under a hydrogen atmosphere with the addition of a catalyst.
• the solvent may be any of those which do not inhibit the progress of the reaction significantly, and examples thereof may include aliphatic hydrocarbons such as hexane, cyclohexane, or methylcyclohexane; aromatic hydrocarbons such as benzene, xylene, or toluene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, or 1,2-dichloroethane; ethers such as diethyl ether, or chloroethane; ethers such as diethyl ether, dioxane, tetrahydrofuran, or 1,2-dimethoxy ethane; amides such as dimethyl formamide, dimethylacetamide, and the like, nitriles such as acetonitrile, or propionitrile; ketones such as acetone, methyl isobutyl ketone, cyclohexanone, or methyl ethyl ketone
• the catalyst may include palladium catalysts such as palladium-carbon, or palladium hydroxide-carbon, nickel catalysts such as Raney-nickel cobalt catalysts, platinum catalysts, ruthenium catalysts, or rhodium catalysts.
• aldehydes may include formaldehyde, acetaldehyde, propionaldehyde, trifluoroacetaldehyde, difluoroacetaldehyde, fluoroacetaldehyde, chloroacetaldehyde, dichloroacetaldehyde, trichloroacetaldehyde, or bromoacetaldehyde
• ketones may include acetone, perfluoroacetone, or methyl ethyl ketone.
• the reaction pressure may be appropriately selected within the range of 1 atm to 100 atm.
• the reaction temperature may be appropriately selected within the range from -20°C to the reflux temperature of the solvent used.
• the reaction time may be appropriately selected within the range from several minutes to 96 hours.
• a compound represented by Formula (15) can be prepared by reacting the compound represented by Formula (14) with an aldehyde or a ketone in a solvent, and treating the product with a reducing agent.
• the solvent may be any of those which do not inhibit the progress of the reaction significantly, and examples thereof may include aliphatic hydrocarbons such as hexane, cyclohexane, or methylcyclohexane; aromatic hydrocarbons such as benzene, xylene, or toluene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, or 1,2-dichloroethane; ethers such as diethyl ether, dioxane, tetrahydrofuran, or 1,2-dimethoxy ethane; amides such as dimethyl formamide, or dimethylacetamide; nitriles such as acetonitrile, or propionitrile; ketones such as acetone, methyl isobutyl ketone, cyclohexanone, or methyl ethyl ketone; esters such as ethyl acetate, or butyl acetate;
• Examples of the reducing agent may include, for example, borohydrides such as sodium borohydride, sodium cyanoborohydride, or sodium triacetate borohydride
• aldehydes may include formaldehyde, acetaldehyde, propionaldehyde, trifluoroacetaldehyde, difluoroacetaldehyde, fluoroacetaldehyde, chloroacetaldehyde, dichloroacetaldehyde, trichloroacetaldehyde, or bromoacetaldehyde.
• ketones may include acetone, perfluoroacetone, or methyl ethyl ketone.
• the reaction temperature may be appropriately selected within the range from -20°C to the reflux temperature of the solvent used. Further, the reaction time may be appropriately selected within the range from several minutes to 96 hours.
• a compound of Formula (15) can be prepared by reacting the compound represented by Formula (14) with an aldehyde in a solvent or without a solvent.
• the solvent may be any of those which do not inhibit the progress of the reaction significantly, and examples thereof may include aliphatic hydrocarbons such as hexane, cyclohexane, or methylcyclohexane; aromatic hydrocarbons such as benzene, xylene, or toluene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, or 1,2-dichloroethane; ethers such as diethyl ether, dioxane, tetrahydrofuran, or 1,2-dimethoxyethane; amides such as dimethyl formamide, or dimethylacetamide; nitriles such as acetonitrile, or propionitrile; ketones such as acetone, methyl isobutyl ketone, cyclohexanone, or methyl ethyl ketone; esters such as ethyl acetate, or butyl acetate; alcohol
• aldehydes may include formaldehyde, acetaldehyde, or propionaldehyde.
• the reaction temperature may be appropriately selected within the range from -20°C to the reflux temperature of the solvent used, and the reaction time may be appropriately selected within the range from several minutes to 96 hours.
• An aromatic carboxamide derivative represented by Formula (1) can be prepared by reacting the aromatic amine derivative represented by Formula (15) with the carboxylic acid derivative or the carbonate ester derivative having a leaving group represented by Formula (16) in a suitable solvent.
• a suitable base or solvent can be used, and as the base or solvent, those exemplified in 1-(i) can be used.
• the reaction temperature, or the reaction time may include those exemplified in 1-(i).
• the carbonyl chloride derivative can be prepared easily from a carboxylic acid derivative by a general method using a halogenating agent.
• the halogenating agent may include those exemplified in 1-(i).
• a compound represented by Formula (18) can be prepared by reacting the compound represented by Formula (17) with a compound represented by Formula (12) under the condition described in 1-(i).
• a compound represented by Formula (15) can be prepared by carrying out an amination reaction using an amination agent such as ammonia, according to the conditions described, for example, in J. Org. Chem. p. 280 (1958 ).
• an amination agent such as ammonia
• the conditions such as a reaction solvent, are not restricted to those described in the literature, and an inert solvent which does not inhibit the proper progress of the reaction significantly may be used.
• the reaction temperature and reaction time may be suitably selected as the reaction proceeds.
• examples of the amination agent include methylamine, or ethylamine in addition to ammonia.
• the compound represented by Formula (1) can be prepared by reacting the compound represented by Formula (15) with a compound represented by Formula (16) according to the conditions described in 1-(i).
• a compound represented by Formula (20) can be prepared by reacting the compound represented by Formula (19) and the compound represented by Formula (12) according to the conditions described in 1-(i).
• a compound represented by Formula (21) can be prepared by reacting the nitro aromatic carboxamide derivative represented by Formula (20) with a suitable fluorinating agent in a suitable solvent or without a solvent.
• the solvent may be any of those which do not inhibit the progress of the reaction significantly, and examples thereof may include aliphatic hydrocarbons such as hexane, cyclohexane, or methylcyclohexane; aromatic hydrocarbons such as benzene, toluene, or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, or 1,2-dichloroethane; chained or cyclic ethers such as diethyl ether, dioxane, tetrahydrofuran, or 1,2-dimethoxy ethane; esters such as ethyl acetate, or butyl acetate; ketones such as acetone, methyl isobutyl ketone, cyclohexanone, or methyl ethyl ketone; nitriles such as acetonitrile, or propionitrile; and aprotic polar solvents such
• These solvents may be used alone or as a mixture of two or more kinds thereof.
• fluorinating agent may include 1,1,2,2-tetrafluoroethyl diethylamine, 2-chloro-1,1,2-trifluoroethyl diethylamine, trifluorodiphenylphospholane, difluorotriphenylphospholane, fluoroformic acid esters, sulfur tetrafluoride, potassium fluoride, potassium hydrogen fluoride, cesium fluoride, rubidium fluoride, sodium fluoride, lithium fluoride, antimony (III) fluoride, antimony (V) fluoride, zinc fluoride, cobalt fluoride, lead fluoride, copper fluoride, mercury (II) fluoride, silver fluoride, silver fluoroborate, thallium (I) fluoride, molybdenum (VI) fluoride, arsenic (III) fluoride, bromine fluoride, selenium tetrafluoride, tris(dimethylamino)sulfonium difluor
• the fluorinating agent may be appropriately selected and used as a solvent, in the range of 1-fold molar equivalent to 10-fold molar equivalents with respect to the nitro aromatic carboxamide derivative represented by Formula (20).
• Additives may be used, and examples thereof may include crown ethers such as 18-crown-6; phase transfer catalysts such as a tetraphenylphosphonium salt; inorganic salts such as calcium fluoride, or calcium chloride; metal oxides such as mercury oxide; ion exchange resins. These additives may not only be added to the reaction system but also used as a pretreating agent for the fluorinating agent.
• the reaction temperature may be appropriately selected within the range from -80°C to the reflux temperature of the solvent used, and the reaction time may be appropriately selected within the range from several minutes to 96 hours.
• a carboxylic acid having an acylamino group represented by Formula (23) can be prepared by reacting a compound represented by Formula (22) as a starting material with a compound represented by Formula (16) according to the conditions described in 1-(i).
• the compound represented by Formula (25) can be prepared by reacting the amide compound represented by Formula (23) with the compound having a leaving group such as a halogen, represented by Formula (24) in a solvent or without a solvent.
• a suitable base or solvent can be used, and as the base or solvent, those exemplified in 1-(i) can be used.
• the reaction temperature, or reaction time may include those exemplified in 1-(i).
• the compound represented by Formula (26) can be prepared from the compound represented by Formula (25) through hydrolysis conducted by a general technique or a method using a Pd catalyst.
• the compound can be obtained by base hydrolysis using one equivalent to 5-fold molar amount of aqueous or alcoholic lithium hydroxide, sodium hydroxide, or potassium hydroxide in a single solvent of methanol, ethanol, tetrahydrofuran, or dioxane, or a combination thereof.
• hydrolysis can be conducted with the combination of a base such as aqueous sodium hydroxide, potassium hydroxide, or lithium hydroxide and a phase-transfer catalyst such as tetrabutylammonium bromide, benzyltriethylammonium chloride, or crown ether.
• a base such as aqueous sodium hydroxide, potassium hydroxide, or lithium hydroxide
• a phase-transfer catalyst such as tetrabutylammonium bromide, benzyltriethylammonium chloride, or crown ether.
• acid hydrolysis can be conducted with inorganic acid such as hydrochloric acid and sulfuric acid, organic acid such as acetic acid and trifluoroacetic acid, or strongly acidic resin.
• the reaction temperature may be appropriately selected in the range from -20°C to the reflux temperature of the solvent to be used.
• the reaction time may be appropriately selected in the range from a few minutes to 96 hours.
• the method using Pd can include, for example, the method described in Tetrahedron Letters p.4371 (1987 ).
• the conditions such as the solvent and the reaction temperature are not limited to those described in the reference.
• the compound represented by Formula (27) can be prepared according to the known routine procedure in which the compound represented by Formula (26) is reacted with thionyl chloride, oxalyl chloride, phosgene, phosphorus oxychloride, phosphorus pentachloride, phosphorous trichloride, thionyl bromide, phosphorus tribromide, or diethylaminosulfur trifluoride.
• the compound represented by Formula (1) can be produced by reacting the compound represented by Formula (27) with the compound represented by Formula (12) according to the conditions described in 1-(i).
• the amide derivative represented by Formula (1) can be produced by reacting the compound represented by Formula (26) with the compound represented by Formula (12) according to the conditions of the method in which a condensing agent is used or the mixed anhydride method both described in 1-(i).
• the compound represented by Formula (29) can be produced by fluorinating the compound represented by Formula (28) according to the conditions described in 3-(ii).
• the compound represented by Formula (30) can be produced by reducing the compound represented by Formula (29) according to the conditions described in 1-(ii).
• a desired product may be isolated from the reaction system after the reaction is completed according to a general method, but if required, purification can be carried out by operations such as recrystallization, column chromatography, or distillation.
• the desired product can be also provided to the subsequent reaction process without being separated from the reaction system.
• Me represents a methyl group
• n-Pr represents a normal propyl group
• CF3 represents a trifluoromethyl group
• C2F5 represents a pentafluoroethyl group
• n-C3F7 represents a heptafluoronormalpropyl group
• H represents a hydrogen atom
• F represents a fluorine atom
• Cl represents a chlorine atom
• Br represents a bromine atom
• I represents an iodine atom, respectively.
• Table 3 shows the physical properties of the representative compounds of the amide derivative according to the present invention.
• the 1 H-NMR chemical shift values shown therein are based on tetramethylsilane as an internal standard substance unless specified otherwise.
• Table 3(1) compound 1 H-NMR (CDCl 3 , ppm) 6-1104 ⁇ 7.40 (1H, t, J 7.8Hz), 7.53-7.64 (3H, m), 7.89 (2H, s), 7.90-7.95 (3H, m), 8.11-8.14 (2H, m), 8.69-8.70 (1H, m).
• 6-1262 ⁇ 7.30-7.33(1 H, m), 7.40-7.44(1 H, m), 7.52-7.55(2H, m), 7.64-7.70(3H, m), 7.95-7.96(1 H, m), 8.09-8.13(2H, m), 8.67-8.68(1H, m). 6-1263 ⁇ 7.20-7.26 (3H, m), 7.38-7.42 (1H, m), 7.91-7.98 (3H, m), 8.07-8.12 (3H, m), 8.63-8.67 (1H, m).
• animal parasites that can be exterminated by the composition for exterminating animal parasites according to the invention include the followings, although the invention is not limited thereto.
• the ectoparasites include Siphonaptera pests such as Ctenocephalides felis , Ctenocephalides canis , Xenopsylla cheopis , Echidnophaga gallinacea), and Pulex irritans ; acarine pests such as Haemaphysalis longicornis Haemaphysalis japonica , Rhipicephalus sanguineus, Boophilus microplus, Dermacentor recticulatus , Dermacentor taiwanensis , Haemaphysalis flava , Ixodes ovatus , Ixodes persulcatus , Amblyomma americanum , Amblyomma maculatum , Dermacentor andersoni , Dermacentor occidentalis , Dermacentor variabilis , Haemaphysalis campanulata , Haemaphysalis megaspinosa , Ixodes n
• the endoparasites include:
• said animal parasites are preferably ectoparasites from the viewpoint of parasiticidal activity, and they are preferably at least one of Siphonaptera pests (especially preferably Ctenocephalides felis ) and Acarina pests (especially preferably Haemaphysalis longicornis , Rhipicephalus sanguineus , and Boophilus microplus ).
• the animals to which the composition for exterminating animal parasites according to the invention can be applied include domestic animals such as horses, cows, pigs, sheep, goats, rabbits, camels, buffalos, deer, minks, and chinchillas; fowls such as chickens, ducks, geese, and turkeys; pets such as dogs, cats, small birds, and monkeys; laboratory animals such as rats, mice, golden hamsters, and guinea pigs; (it is preferable to exclude humans) although the invention is not limited thereto.
• domestic animals such as horses, cows, pigs, sheep, goats, rabbits, camels, buffalos, deer, minks, and chinchillas
• fowls such as chickens, ducks, geese, and turkeys
• pets such as dogs, cats, small birds, and monkeys
• laboratory animals such as rats, mice, golden hamsters, and guinea pigs
• composition for exterminating animal parasites according to the invention can be used as a parasiticide by any of the methods normally used, with no particular restriction.
• the composition may be dissolved, suspended, mixed, impregnated, adsorbed, or adhered on suitable solid and/or liquid carriers according to a formulation generally used, and, if required, together with adjuvant in a suitable proportion.
• the composition may be prepared into an appropriate form in accordance with the intended use.
• the solid or liquid carrier for use in the invention may be those normally used in agents for animals. From the viewpoint of easiness of treatment on the target animals, it is preferable to use a liquid carrier.
• the liquid carrier includes, for example, alcohol such as methyl alcohol, ethyl alcohol, isopropyl alcohol, tertiary butyl alcohol, and benzyl alcohol; propylene carbonate; N-methyl-2-pyrrolidone; and water.
• alcohol such as methyl alcohol, ethyl alcohol, isopropyl alcohol, tertiary butyl alcohol, and benzyl alcohol
• propylene carbonate propylene carbonate
• N-methyl-2-pyrrolidone and water.
• surfactant surfactant, antioxidant, or emulsifier
• the adjuvant can include, for example, surfactant such as polyoxyethylene alkylaryl ether, polyoxyethylene sorbitan monolaurate, alkyl allyl sorbitan monolaurate, alkylbenzenesulfonate, alkylnaphthalene sulfonic acid, ligninsulfonic acid salts, higher alcohol sulfate salts, glycol monoalkyl ethers, and glycols; emulsifier such as sorbitan monooleate, sorbitan monolaurate, caprylic acid monoglyceride, capric acid monoglyceride, isostearic acid monoglyceride, and propylene glycol monocaprylate; and antioxidant such as BHA and BHT.
• surfactant such as polyoxyethylene alkylaryl ether, polyoxyethylene sorbitan monolaurate, alkyl allyl sorbitan monolaurate, alkylbenzenesulfonate, alkylnaphthalen
• composition for exterminating animal parasites according to the invention may be administered orally or parenterally to an animal.
• the composition for exterminating animal parasites according to the invention may be in the form of capsules, tablets, pills, powders, granules, fine granules, syrups, enteric agents, suspensions, paste, or beverage or feeds mixed with the drug.
• the composition for exterminating animal parasites according to the invention may be in the form of injectables, drips, suppositories, emulsions, suspensions, drops, ointments, creams, solutions, lotions, sprays, aerosols, cataplasms, and tapes.
• the method for administration includes the spot-on method in which drops are dropped on the skin of the back shoulder region of the target animal to exterminate ectoparasites; local methods such as the pour-on method in which a liquid agent is applied along the back center line of the target animal to allow the applied agent to diffuse on the body surface, resulting in control of ectoparasites; the methods in which the agent is released from a collar containing the agent; the methods in which a liquid agent, or ointment is directly applied to the body surface; the methods in which an aerosol is applied with a spray; the methods in which an injectable is injected intramuscularly, or subcutaneously; and rectal administration with a suppository.
• the composition for exterminating animal parasites according to the invention also can prophylactically prevent parasitic infections by applying it to the environments which are to be the infection routes.
• the composition can prevent soil infections from soils of upland fields and parks; percutaneous infections from aqueous systems such as river, lake, wetland, and paddy field; oral infections from excrements of animals such as dogs and cats; and oral infections from raw meats of sea water fish, fresh water fish, Crustaceae, shellfish, or domestic animals; and infections from mosquitoes, horseflies, flies, cockroaches, ticks, fleas, lice, assassin bugs, or chiggers.
• the optimal dosage varies depending on whether it is used for therapeutic purposes or for preventive purposes, and also varies with the type of infected parasites, the type and extent of infection, or dosage form. But generally, in case of oral administration, the dosage is in the range from about 0.0001 to 10,000 mg per kilogram of body weight per day. In case of parenteral administration, the dosage is in the range from about 0.0001 to 10,000 mg per kilogram of body weight per day, and the composition is administered in single or in divided doses.
• the concentration of the active ingredient in the composition for exterminating animal parasites according to the invention is typically from 0.0001 to 100% by weight, preferably from 0.001 to 99% by weight, and more preferably from 0.005 to 80% by weight.
• the parasiticides may be provided as a high-concentrated composition to be diluted to the appropriate concentration prior to use.
• the composition for exterminating animal parasites according to the invention can further contain other insecticidal components that are generally known.
• the other insecticidal components can include, for example, pyrethroid compounds such as permethrin, d-phenothrin, allethrin, pyrethrum, prallethrin, cyphenothrin, cyfluthrin, fenvalerate, fenpropathrin, transfluthrin, metofluthrin, resmethrin, cypermethrin, alpha-cypermethrin, bifenthrin, deltamethrin, lambda-cyhalothrin, d,d-trans-cyphenothrin, tetramethrin, and ethofenprox; organic phosphorus compounds such as dichlorvos, tetrachlorvinphos, fenthion
• DMF means N,N-dimethyl formamide
• THF means tetrahydrofuran
• IPE isopropyl ether
• DMI means 1,3-dimethyl-2-imidazolidinone.
• the solvent of the organic layer was evaporated under reduced pressure, and 500 ml of ethyl acetate was charged thereto.
• 160 g (0.608 mol) of a 4 M hydrogen chloride/ethyl acetate solution was added dropwise thereto, followed by stirring at room temperature for 30 minutes, and then stirring at 5°C for 1 hour.
• the filtrate was washed with water and a saturated aqueous sodium hydrogen carbonate in this order, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
• the filtrate was extracted with ethyl acetate, and the organic layer was washed with a 20% aqueous sodium hydroxide solution and saturated brine, and then dried over anhydrous magnesium sulfate.
• the organic layer was washed with 1 M hydrochloric acid, water, and a saturated aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate.
• the solvent was evaporated under reduced pressure, and 500 ml of ethyl acetate was charged thereto. 255 g (1.02 mol) of a 4 M hydrogen chloride/ethyl acetate solution was added dropwise thereto, followed by stirring at room temperature for 30 minutes and at 5°C for 1 hour.
• a target compound was prepared from 2,6-dibromo-4-(perfluoropropan-2-yl)aniline.
• a target compound was prepared from 2-chloro-N-(2,6-dibromo-4-(perfluoropropan-2-yl)phenyl)-3-nitrobenzamide.
• a target compound was prepared from N-(2,6-dibromo-4-(perfluoropropan-2-yl)phenyl)-2-fluoro-3-nitrobenzamide.
• a target compound was prepared from 3-amino-N-(2,6-dibromo-4-(perfluoropropan-2-yl)phenyl)-2-fluorobenzamide.
• a target compound was prepared from N-(2,6-dibromo-4-(perfluoropropan-2-yl)phenyl)-2-fluoro-3-(methylamino)benzamide and benzoyl chloride.
• 1 H-NMR (CDCl 3 , ppm) ⁇ 3.51 (3H, s), 7.22-7.44 (7H, m), 7.86 (2H, s), 8.00-8.03 (2H, m).
• a target compound was prepared from 2-chloro-N-(2,6-diiodo-4-(perfluoropropan-2-yl)phenyl)-3-nitrobenzamide.
• 1 H-NMR (CDCl 3 , ppm) ⁇ 7.52-7.55 (1H, m), 8.12-8.18 (3H, m), 8.29-8.32 (1H, m), 8.48-8.51 (1H, m).
• a target compound was prepared from N-(2,6-diiodo-4-(perfluoropropan-2-yl)phenyl)-2-fluoro-3-nitrobenzamide.
• a target compound was prepared from 3-amino-N-(2,6-diiodo-4-(perfluoropropan-2-yl)phenyl)-2-fluorobenzamide.
• the organic layer of the liquid was washed with water and a saturated aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate.
• the obtained solid was washed with hexane to prepare 0.840 g (yield 51%) of a target compound.
• a target compound was prepared from 2-iodo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)aniline and 2-chloro-3-nitrobenzoyl chloride.
• a target compound was prepared from 2-chloro-N-(2-iodo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-3-nitrobenzamide.
• a target compound was prepared from 2-fluoro-N-(2-iodo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-3-nitrobenzamide.
• a target compound was prepared from 3-amino-2-fluoro-N-(2-iodo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)benzamide.
• a target compound was prepared from 2-fluoro-N-(2-iodo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-3-(methylamino)benzamide and 4-fluorobenzoyl chloride.
• a target compound was prepared from 2-fluoro-N-(2-iodo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-3-(methylamino)benzamide which was obtained in 4-5 of example 4 and 3-fluorobenzoyl chloride.
• 1 H-NMR (CDCl 3 , ppm) ⁇ 3.50 (3H, s), 6.91 (2H, s), 7.00-7.18 (4H, m), 7.27-7.31 (1H, m), 7.45-7.48 (1H, m), 7.93 (1H, s), 8.01-8.03 (1H, m), 8.12 (1H, broad-s), 8.34 (1H, s).
• a target compound was prepared from 3-amino-2-fluoro-N-(2-iodo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)benzamide which was obtained in 4-4 of example 4 and 4-fluorobenzoyl chloride.
• the amide derivatives of Compound No. 7-1574 and 7-1104 were found to be effective even in the examination after 12 hours of the exposure. In addition, they showed immediate effect as compared with the fipronil.
• Insecticidal Test for Haemaphysalis longicornis 1 ml of a solution of acetone, the active ingredient, prepared to the prescribed concentration was added dropwise to filter paper inside a petri dish with a diameter of 9 cm, and the acetone was evaporated at room temperature. About 100 larvae of Haemaphysalis longicornis per dish were added to the filter paper. The dish was covered by a polyethylene sheet, sealed with a rubber band, and placed in a dark place at a temperature of 25°C and a relative humidity of 100% to expose the larvae to the test substance. After 24 hours of the exposure, the conditions of the larvae were examined and classified into "alive” and "dead (including a moribund condition)".
• the amide derivatives according to the invention were found to be effective in killing Haemaphysalis longicornis.
• composition for exterminating animal parasites according to the invention has excellent activity for exterminating animal parasites, the composition has wide industrial applicability.

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